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Aspirin for venous thromboembolism prevention and treatment: a renewal?

BOUNAMEAUX, Henri, FONTANA, Pierre

BOUNAMEAUX, Henri, FONTANA, Pierre. Aspirin for venous thromboembolism prevention and treatment: a renewal? Polskie Archiwum Medycyny Wewnetrznej , 2012, vol. 122, no. 10, p.

461-3

PMID : 23123525

Available at:

http://archive-ouverte.unige.ch/unige:26367

Disclaimer: layout of this document may differ from the published version.

1 / 1

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EDITORIAL Aspirin for venous thromboembolism prevention and treatment: a renewal? 461 Over the past months, aspirin has suddenly moved

from the backstage to the front of the scene of venous thromboembolism. Indeed, two features raised interest of the medical community. First, in 2012, the American College of Chest Physicians (ACCP) evidence‑based clinical practice guide‑

lines changed its former strong recommendation (Grade 1A) against use of aspirin for preventing venous thromboembolism after major orthopedic surgery1 for a conditional Grade 1B recommen‑

dation in favor of its use in this particular indica‑

tion.2 Second, The New England Journal of Medicine has recently published the results of the Warfa‑

rin and Aspirin (WARFASA) study that convinc‑

ingly demonstrate the efficacy of low‑dose aspi‑

rin for preventing the long‑term recurrence of ve‑

nous thromboembolism in patients who received a course of 6 to 18 months of oral anticoagulant treatment for the initial event.3 These features are in line with recent basic science data that empha‑

size the role of platelets in the pathogenesis of ve‑

nous thrombosis. Indeed, the histological inspec‑

tion of venous thrombi shows that cells such as red blood cells and leukocytes are in close vicin‑

ity of platelets. Of note, neutrophils stimulated with proinflammatory agents or activated plate‑

lets release their nuclear content (including his‑

tones) that form web‑like structures designated as neutrophil extracellular traps,4 which in turn promote the generation of thrombin through platelet‑dependent mechanisms5 as well as vein thrombi, at least in a murine model.6 Taken to‑

gether, these findings provide a rationale for clin‑

ical studies addressing the issue of the prevention of venous thrombosis by platelet function inhib‑

itors, particularly aspirin.

However, both the new ACCP recommendation about thromboprophylaxis in major orthopedic surgery with the suggestion of aspirin as an al‑

ternative to anticoagulants, and the superiority of aspirin over placebo for secondary prophylax‑

is after a first venous thromboembolic event are essentially each based on a single study. In 2000,

the Pulmonary Embolism Prevention (PEP) in‑

vestigators7 reported a significant risk reduc‑

tion with aspirin 160 mg daily compared with placebo for symptomatic venous thromboem‑

bolism in a very large population undergoing surgery for hip fractures or elective hip arthro‑

plasty. In the WARFASA multicenter, investigator‑

‑initiated, double‑blind study, Beccatini et al.3 con‑

cluded that aspirin is efficacious and safe for sec‑

ondary long‑term prophylaxis of venous throm‑

boembolism in patients who had experienced a first unprovoked deep vein thrombosis (DVT) or pulmonary embolism.

Let us first consider the issue of aspirin for thromboprophylaxis in major orthopedic sur‑

gery. As early as 1994, the Antiplatelet Trialists’

Collaboration meta‑analysis8 pooled data from 62 randomized studies totaling over 8000 pa‑

tients and concluded that aspirin (various dosag‑

es) reduced the frequency of both pulmonary em‑

bolism (by two‑thirds) and DVT (by 40%). How‑

ever, the methodological quality of many studies included in the meta‑analysis was poor, and di‑

agnostic methods were far from optimal, which resulted in mixed opinions on its results. There‑

fore, the PEP trial was launched in the mid‑1990s to test aspirin (160 mg daily for 35 days) vs. pla‑

cebo in 17,444 patients with hip fracture or elec‑

tive hip arthroplasty. The study had several meth‑

odological strengths, including a central random‑

ization, a double‑blind design, an independent blinded committee for adjudicating objectively confirmed endpoints, and a follow‑up that was close to 100%. There was a statistically significant 28% but limited relative risk reduction in symp‑

tomatic DVT (relative risk [RR], 0.72; 95% confi‑

dence interval [CI], 0.53–0.96) with no beneficial effect on nonfatal pulmonary embolism, and no significant effect on overall mortality. The num‑

ber needed to treat (NNT) to prevent one symp‑

tomatic DVT was 238 (P = 0.03). Despite the large sample size, major nonfatal bleeding was not sig‑

nificantly increased in patients given aspirin even

Correspondence to:

Prof. Henri Bounameaux, MD, Division of Angiology and Hemostasis, University Hospitals of Geneva, Rue Michel Servet, 1 CH‑1211 Geneva 4, Switzerland, phone: +41‑22‑3795033, fax: +41‑22‑3795002, e‑mail: henri.bounameaux@unige.ch Received: September 26, 2012.

Accepted: September 27, 2012.

Conflict of interest: none declared.

Pol Arch Med Wewn. 2012;

122 (10): 461‑463

Copyright by Medycyna Praktyczna, Kraków 2012

EDITORIAL

Aspirin for venous thromboembolism prevention and treatment: a renewal?

Henri Bounameaux, Pierre Fontana

Division of Angiology and Hemostasis, University Hospitals of Geneva, Geneva, Switzerland

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POLSKIE ARCHIWUM MEDYCYNY WEWNĘTRZNEJ 2012; 122 (10) 462

in patients with a first idiopathic DVT and/or pul‑

monary embolism, as tested in the WARFASA study.3 In this trial, 205 patients were random‑

ized to receive aspirin 100 mg daily and 197 pa‑

tients were given placebo. Twenty‑eight (6.6%

per year) and 43 (11.2% per year) symptomatic venous thromboembolic events were adjudicat‑

ed in the two groups, respectively, during a medi‑

an follow‑up of 2 years, resulting in a hazard ra‑

tio of 0.58 (95% CI, 0.36–0.93) (P = 0.02). Only 1 patient in each group experienced a major bleed‑

ing episode.

These results need to be viewed in the perspec‑

tive of other large‑scale, randomized controlled studies of long‑term secondary prevention of venous thromboembolism recurrence – the Pre‑

vention of Recurrent Venous Thromboembolism (PREVENT) study,9 the EINSTEIN Extension study,10 and the Extended Low‑Intensity Antico‑

agulation for Thromboembolism (ELATE) study.11 Both PREVENT and EINSTEIN Extension were placebo‑controlled trials while ELATE compared 2 intensities of warfarin therapy (TABLE). In all these studies, the main efficacy outcome was re‑

current symptomatic, objectively confirmed DVT or pulmonary embolism. The active regimen in PREVENT and EINSTEIN Extension was warfarin with a target international normalized ratio (INR) of 1.5–2.0 and rivaroxaban (20 mg once daily, p.o), respectively. While the relative risk reduction of venous thromboembolism recurrence was 64%

(95% CI, 19%–67%) and 82% (95% CI, 61%–91%), respectively, in these 2 trials, it was only 42% in WARFASA with a large CI (95% CI, 7%–64%).

Even though the CIs in the 3 studies largely though there was a trend in this direction (RR,

1.12; 95% CI, 0.94–1.34). Of note, a substan‑

tial proportion of the PEP population also re‑

ceived some sort of heparin, which may have off‑

set the effect of aspirin. Altogether, the PEP tri‑

al confirmed a statistically significant but small thromboprophylactic effect of aspirin in major or‑

thopedic surgery (mainly hip fracture) compared with placebo. Based on this evidence, the 8th ACCP consensus1 admitted that aspirin provides some protection against venous thromboembo‑

lism, but did not recommend its use alone as pro‑

phylaxis primarily because more effective meth‑

ods are readily available, e.g., low‑dose unfrac‑

tionated heparin and low‑molecular‑weight hep‑

arins (LMWH). This nuanced appreciation was, however, translated into a strong recommenda‑

tion against aspirin. In turn, the 9th edition of the ACCP consensus concentrated their analysis on the so called patient‑important (say symptom‑

atic) outcomes and, therefore, rehabilitated aspi‑

rin as one prophylactic agent among others for patients undergoing major orthopedic surgery.

However, the panelists state in the text that in‑

direct evidence from trials of LMWH and aspirin against placebo also shows greater relative effi‑

cacy of LMWH and, in the end, suggest the use of LMWH in preference to the other options in‑

cluding aspirin. The controversy raised around the contradiction between the 8th and the 9th ACCP consensus recommendations thus seems to be largely artificial.

Let us now consider the issue of aspirin for long‑term secondary prophylaxis after an initial 6‑ to 18‑month period of anticoagulant treatment

TABLE Randomized controlled studies of long‑term secondary prevention of venous thromboembolism recurrence after an initial course of anticoagulant treatment

Study Number of

patients Investigational regimen arm (event rate, %/y) RRR

Comparator regimen arm (event rate, %/y)

VTE recurrence (RR, 95% CI) P

NNT

Major bleeding (RR, 95% CI) P

NNH Ridker et al.9

(PREVENT study)

508 warfarin

INR 1.5–2 (2.6) 64%

placebo (7.2)

0.36 (0.19–0.67)

<0.001 22

2.53 (0.49–13.03) 0.25 200 EINSTEIN

Investigators10 1196 rivaroxaban (1.3) 82%

placebo (7.1)

0.18 (0.09–0.39)

<0.001 17

0.7% (Riva) vs. 0 (placebo) 0.11 143 Beccatini et al.3 402 aspirin

(6.6) 41%

placebo (11.2)

0.58 (0.36–0.93) 0.02 22

0.3% in both arms 0.97 indefinite Kearon et al.11

(ELATE study) 738 warfarin INR 1.5–1.9 (1.9) NA

warfarin INR 2–3 (0.7)

2.8 (1.1–7.0) 0.03 NA

1.2 (0.4–3.0) 0.76 NA

Abbreviations: CI – confidence interval, INR – international normalized ratio, NA – not applicable, NNH – number needed to harm, NNT – number needed to treat, RR – relative risk, RRR – relative risk reduction (compared with placebo), VTE – venous thromboembolism

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EDITORIAL Aspirin for venous thromboembolism prevention and treatment: a renewal? 463

Semeraro F, Ammollo CT, Morrissey JH, et al. Extracellular histones pro‑

5

mote thrombin generation through platelet‑dependent mechanisms: involve‑

ment of platelet TLR2 and TLR4. Blood. 2011; 118: 1952-1961.

Brill A, Fuchs TA, Savchenko AS, et al. Neutrophil extracellular traps 6

promote deep vein thrombosis in mice. J Thromb Haemost. 2012; 10:

136‑144.

Prevention of pulmonary embolism and deep vein thrombosis with low 7

dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet. 2000; 355:

1295‑1302.

Collaborative overview of randomized trials of antiplatelet therapy – III:

8

Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. Antiplatelet Trialists’ Col‑

laboration. BMJ. 1994; 308: 235-246.

Ridker PM, Goldhaber SZ, Danielson E, et al.; PREVENT investigators.

9

Long‑term, low‑intensity warfarin therapy for the prevention of recurrent ve‑

nous thromboembolism. N Engl J Med. 2003; 348: 1425-1434.

Bauersachs R, Berkowitz SD, Brenner B, et al.; EINSTEIN Investigators.

10

Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med.

2010; 363: 2499‑2510.

Kearon C, Ginsberg JS, Kovacs MJ, et al.; Extended Low-intensity An‑

11

ticoagulation for Thrombo-Embolism Investigators (ELATE). Comparison of low‑intensity warfarin therapy with conventional‑intensity warfarin thera‑

py for long‑term prevention of recurrent venous thromboembolism. N Engl J Med. 2003; 349: 631-639.

Kearon C, O’Donnell M. Graduated compression stockings to prevent 12

venous thromboembolism in hospital: evidence from patients with acute stroke. Pol Arch Med Wewn. 2011; 121: 40‑43.

overlap, its lower limit in WARFASA is compat‑

ible with almost no effect of aspirin. Admitted‑

ly, the NNT was very similar in the 3 placebo‑

‑controlled trials but for WARFASA this is mainly due to the high rate of events in the placebo group:

11.2% per year, compared with 7.2% and 7.1% in PREVENT and EINSTEIN Extension, respective‑

ly. There is no obvious reason for this difference since all trials included selected patients who had already been treated with anticoagulants during a prolonged period, and who were at low risk of bleeding. Cancer was rare in these populations and was an exclusion criterion for WARFASA. Be‑

cause of the relatively small number of patients in the latter study, the margin of error around these 11.2% is quite high, and the aspirin effect may be overestimated. As a matter of fact, the in‑

cidence of recurrent venous thromboembolism in the active groups was 2.6% (PREVENT), 1.3%

(EINSTEIN Extension), 1.9% (ELATE, low‑in‑

tensity INR), and 0.7% (ELATE, standard‑inten‑

sity INR), as compared with 6.6% in WARFASA.

The ongoing placebo‑controlled Aspirin to Prevent Recurrent Venous Thromboembolism (ASPIRE) study (ACTRN012 605 000 004 662) with more than 800 patients and the planned prespeci‑

fied pooled analysis of WARFASA and ASPIRE (ACTRN12 611 000 684 921) should reduce this imprecision and provide the final word about the extent of the aspirin effects in the indication of long‑term secondary prevention in patients with first idiopathic venous thromboembolism.

As far as the post orthopedic surgery prophylax‑

is is concerned, the new ACCP recommendations will support to a degree the attitude of many sur‑

geons, especially in the United States, to restrict prophylaxis to aspirin alone or in combination with compression devices2,12 in patients under‑

going major joint arthroplasty. While this policy might apply to selected patients with high bleed‑

ing risk, we doubt that it provides sufficient pro‑

tection against venous thromboembolism and do not use it routinely in our practice. Nowadays, LMWH and, even more, the novel oral anticoag‑

ulants have almost eradicated this complication in providing safer care for this kind of surgery.

Whether aspirin could be an option for extension of prophylaxis in such cases remains hypotheti‑

cal. With respect to long‑term secondary preven‑

tion after venous thrombosis, we feel that aspi‑

rin should still wait a while, which should not be a problem for a hundred‑year‑old drug.

REfEREncEs

Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous throm‑

1

boembolism: American College of Chest Physicians evidence‑based clinical practice guidelines. Chest. 2008; 133 (6 Suppl): 381S‑453S.

Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in or‑

2

thopedic surgery patients: Antithrombotic Therapy and Prevention of Throm‑

bosis, 9th ed: American College of Chest Physicians Evidence‑Based Clinical Practice Guidelines. Chest. 2012; 141 (2 Suppl): e278S‑e325S.

Becattini C, Agnelli G, Schenone A, et al.; WARFASA Investigators. As‑

3

pirin for preventing the recurrence of venous thromboembolism. N Engl J Med. 2012; 366: 1959-1967.

Brinkmann V, Zychlinsky A. Beneficial suicide: why neutrophils die to 4

make NETs. Nat Rev Microbiol. 2007; 5: 577-582.

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